Bupropion metabolites and methods of their synthesis and use

ABSTRACT

Methods and compositions are disclosed which utilize metabolites of bupropion for treating disorders ameliorated by inhibition of neuronal monoamine reuptake. Such disorders include, but are not limited to, erectile dysfunction, affective disorders, cerebral function disorders, cigarette smoking, and incontinence. The invention further discloses methods of making optically pure bupropion metabolites.

FIELD OF THE INVENTION

[0001] This invention relates to synthesis of, methods of using, andcompositions comprising bupropion metabolites and isomers thereof.

BACKGROUND OF THE INVENTION

[0002] Bupropion, a racemic mixture of (+)- and(−)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone, is anantidepressant of the aminoketone class, and is described in U.S. Pat.Nos. 3,819,706 and 3,885,046. The hydrochloride salt of bupropion issold under the trade names WELLBUTRIN® and WELLBUTRIN SR® for thetreatment of depression. Bupropion is also sold under the trade nameZYBAN® as a drug useful to achieve smoking cessation. Additionalbenefits of bupropion maleate are reported in European PatentApplication No. 118036.

[0003] Although its mechanism of action is poorly understood, bupropionis reportedly a weak but selective inhibitor of dopamine. Its potency asan inhibitor of norepinephrine reuptake is reportedly only half of thatfor dopamine, and it shows little affinity for the serotonergictransport system. Ascher, J. A., et al., J. Clin. Psychiatry, 56:395-401(1995).

[0004] Bupropion is extensively metabolized in man and animal. Threemetabolites found in the plasma of healthy humans to which it has beenadministered are shown in Scheme 1:

[0005] Posner, J., et al., Eur. J. Clin Pharmacal., 29:97-103 (1985);Suckow, R. F., et al., Biomedical Chromatography, 11:174-179 (1997).Referring to Scheme 1, metabolite 1 has the chemical name2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; metabolite 2has the chemical name1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol; andmetabolite 3 has the chemical name1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone. Becausebupropion is racemic and its metabolites are chiral, enantiomers of eachof the metabolites 1, 2, and 3 likely exist in human plasma followingits administration.

[0006] The bupropion metabolite 1, often referred to as“hydroxybupropion,” has two chiral carbon atoms and can thus exist astwo pairs of enantiomers. These are shown in Scheme 2:

[0007] Pair 1a is reportedly the most active human metabolite bupropion.Kelley, J. L., et al., J. Med. Chem., 39:347-349 (1996). The mixture 1ahas been isolated from human plasma and allegedly separated into its(S,S) and (R,R) components. Suckow, R. F., et al., BiomedicalChromatography, 11:174-179(1997).

[0008] The amino alcohol metabolite 2 can also exist as two pairs ofenantiomers. The pair wherein the alcohol and amine moieties are ciseach other is commonly referred to as the erythro-amino alcoholmetabolite; the pair wherein the two moieties are trans to each other isreferred to as the threo-amino alcohol metabolite.

[0009] The tert-butyl alcohol metabolite 3 can exist as one of twoenantiomers. This metabolite, the accumulation of which in human plasmacoincides with the elimination of a single dose of bupropion, isbelieved by some to be a precursor to hydroxybupropion. Posner, J., etal., Eur. J. Clin. Pharmacol., 29:97-103 (1985); Suckow, R. F., et al.,Biomedical Chromatography, 11:174-179 (1997).

[0010] Clearly, the metabolism of bupropion, which is complicated andpoorly understood, results in a complex array of optically activecompounds. The structures of these molecules and their chiralityprovides the skilled artisan with difficult issues of asymmetricsynthesis, chiral resolution, and pharmacological activity.

[0011] Bupropion is widely used to treat affective disorders in patientswho do not respond to, or cannot tolerate, other antidepressants such astricyclic agents or monoamine oxidase inhibitors. Examples of affectivedisorders are depression and bipolar manic-depression. Bupropion is alsouseful in the treatment of other diseases or conditions associated withthe reuptake of neuronal monoamines such as serotonin andnorepinephrine. These reportedly include: schizophrenia (U.S. Pat. No.5,447,948); attention-deficit disorder; psycho-sexual dysfunction (U.S.Pat. No. 4,507,323); bulimia and other eating disorders; Parkinson'sdisease; migraine (U.S. Pat. No. 5,753,712); and chronic pain. Bupropionalso reportedly increases success rates in some smoking cessationtreatments. Rose, J. E., Annu. Rev. Med., 47:493-507 (1996); Ferry, L.H. et al., J. Addict. Dis., 13:A9 (1994); and Lief, H. I., Am. J.Psychiatry, 153(3):442 (1996).

[0012] Further uses of bupropion reportedly include the treatment of:the effects of ethanol (U.S. Pat. No. 4,393,078); tardive dyskinesia(U.S. Pat. No. 4,425,363); drowsiness (U.S. Pat. Nos. 4,571,395 and4,798,826); minimal brain dysfunction (U.S. Pat. No. 4,435,449);psychosexual dysfunction (U.S. Pat. No. 4,507,323); prostate hypertrophyand sexual dysfunction (U.S. Pat. No. 4,835,147); psychostimulantaddiction (U.S. Pat. No. 4,935,429); substance abuse (U.S. Pat. No.5,217,987); high cholesterol (U.S. Pat. No. 4,438,138); and weight gain(U.S. Pat. No. 4,895,845).

[0013] Certain advantages exist in using bupropion for the treatment ofdiseases and conditions such as those provided above. For example, itdoes not inhibit monoamine oxidase or block the reuptake of serotonin,unlike other neuronal monoamine reuptake inhibitors. Administration ofbupropion can thus avoid or lessen many of the adverse side effectscommonly associated with other antidepressants such as tricyclic agentsand monoamine oxidase inhibitors.

[0014] Unfortunately, bupropion is not free of adverse effects.Administration of the drug can cause seizures, especially in patientscurrently taking the monoamine oxidase inhibitor phenelzine. Otherfrequently reported adverse effects associated with the use of bupropioninclude nausea, vomiting, excitement, agitation, blurred or blurryvision, restlessness, postural tremor, hallucinations/confusional stateswith the potential for abuse, anxiety, insomnia, headaches and/ormigraines, dry mouth, constipation, tremor, sleeping disturbances,dermatologic problems (e.g., rashes), neuropsychiatric signs andsymptoms (e.g., delusions and paranoia), and weight loss or gain.Physicians' Desk Reference® 1252-1258 (53^(rd) ed. 1999). These effectsare dose limiting in a number of patients, and can be particularlydangerous for Parkinson's patients.

[0015] There thus remains a need for a drug that provides the advantagesof bupropion, but with fewer disadvantages. Compounds and pharmaceuticalcompositions are desired that can be used for the treatment andprevention of disorders and conditions while incurring fewer of theadverse effects associated with bupropion.

SUMMARY OF THE INVENTION

[0016] This invention encompasses methods of making and using bupropionmetabolites and pharmaceutical compositions and dosage forms comprisingbupropion metabolites. In particular, the invention provides methods ofsynthesizing optically pure (S,S) hydroxybupropion and optically pure(R,R)-hydroxybupropion.

[0017] The invention further provides methods of treating and preventingconditions that include, but are not limited to, erectile dysfunction,affective disorders, cerebral function disorders, tobacco smoking, andincontinence. Methods of the invention comprise administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a bupropion metabolite, or apharmaceutically acceptable salt, solvate, or clathrate thereof.Preferred methods of the invention further comprise the use of at leastone additional physiologically active agent such as a selectiveserotonin reuptake inhibitor (“SSRI”), 5-HT₃ antagonist, or nicotinewith a bupropion metabolite.

[0018] Pharmaceutical compositions and dosage forms of the inventioncomprise a therapeutically or prophylactically effective amount of abupropion metabolite and optionally at least one additionalphysiologically active agent such as a SSRI, 5-HT₃ antagonist, ornicotine.

Definitions

[0019] As used herein, the term “patient” includes mammal, whichincludes human.

[0020] As used herein, the term “bupropion metabolite” includes, but isnot limited to,2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol,1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol, and1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone. As usedherein, the term “optically pure bupropion metabolite” includes, but isnot limited to, optically pure:(R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;(S,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;(R,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;(R,R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol;(S,R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol;(S,S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol;(R,S)-1-3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol;(R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; and(S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.

[0021] As used herein to describe a composition, the terms“substantially optically pure,” “optically pure,” and “optically pureenantiomer” mean that the composition contains greater than about 90% ofthe desired stereoisomer by weight, preferably greater than about 95% ofthe desired stereoisomer by weight, and most preferably greater thanabout 99% of the desired stereoisomer by weight, said weight percentbased upon the total weight of bupropion metabolite. As used herein todescribe a composition, the term “substantially free” means that thecomposition contains less than about 10% by weight, preferably less thanabout 5% by weight, and more preferably less than about 1% by weight ofthe undesired stereoisomer.

[0022] As used herein, the term “pharmaceutically acceptable salt”refers to a salt prepared from a pharmaceutically acceptable non-toxicinorganic or organic acid or base. The compounds of the invention thatare basic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. Acids that can be used to preparepharmaceutically acceptable acid addition salts of such basic compoundsof the invention are those that form non-toxic acid addition salts,i.e., salts containing pharmacologically acceptable anions, such as, butnot limited to, hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, formate, acetate,propionate, succinate, camphorsulfonate, citrate, acid citrate,fumarate, gluconate, isethionate, lactate, malate, mucate, gentisate,isonicotinate, saccharate, tartrate, bitartrate, para-toluenesulfonate,glycolate, glucuronate, maleate, furoate, glutamate, ascorbate,benzoate, anthranilate, salicylate, phenylacetate, mandelate, embonate(pamoate), methanesulfonate, ethanesulfonate, pantothenate,benzenesulfonate, stearate, sulfanilate, alginate, p-toluenesulfonate,and galacturonate. Particularly preferred anions are hydrobromide,hydrochloride, phosphate, acid phosphate, maleate, sulfate, and acidphosphate. Most particularly preferred anions are hydrochloride andmaleate.

[0023] Compounds of the invention that are acidic in nature are capableof forming salts with various pharmaceutically acceptable bases. Thebases that can be used to prepare pharmaceutically acceptable baseaddition salts of such acidic compounds of the invention are those thatform non-toxic base addition salts, i.e., salts containingpharmacologically acceptable cations such as, but not limited to, alkalimetal or alkaline earth metal salts and the calcium, magnesium, sodiumor potassium salts in particular. Suitable organic bases include, butare not limited to, N,N-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumaine(N-methylglucamine), lysine, and procaine.

[0024] As used herein, the terms “avoiding adverse side effects” and“avoiding adverse effects” mean eliminating or reducing at least oneadverse effect associated with the administration of a particularcompound or mixture of compounds.

[0025] As used herein, the term “adverse side effects associated withracemic bupropion” includes, but is not limited to, seizures, nausea,vomiting, excitement, agitation, blurred or blurry vision, restlessness,postural tremor, hallucinations/confusional states with the potentialfor abuse, anxiety, insomnia, headaches and/or migraines, dry mouth,constipation, tremor, sleeping disturbances, dermatologic problems(e.g., rashes), neuropsychiatric signs and symptoms (e.g., delusions andparanoia), and weight gain.

[0026] As used herein, the term “adverse side effects associated withthe inhibition of dopamine reuptake” includes, but is not limited to,seizures, nausea, vomiting, excitement, agitation, blurred or blurryvision, restlessness, postural tremor, hallucinations/confusional stateswith the potential for abuse, anxiety, insomnia, headaches and/ormigraines, dry mouth, constipation, tremor, sleeping disturbances,dermatologic problems (e.g., rashes), neuropsychiatric signs andsymptoms (e.g., delusions and paranoia), and weight gain.

[0027] As used herein, the term “disorder ameliorated by the inhibitionof neuronal monoamine reuptake” and “disorder related to reuptake ofneuronal monamines” mean an acute or chronic disease, disorder, orcondition having symptoms that are reduced or alleviated by theinhibition of neuronal monoamine reuptake, and especially by theinhibition of norepinephrine (or noradrenaline) and serotonin reuptake.Disorders ameliorated by inhibition of neuronal monoamine reuptakeinclude, but are not limited to, erectile dysfunction, affectivedisorders, cerebral function disorders, tobacco smoking, andincontinence.

[0028] As used herein, the term “affective disorder” includes, but isnot limited to, depression, anxiety disorders, attention deficitdisorder, attention deficit disorder with hyperactivity, bipolar andmanic conditions, bulimia, obesity or weight-gain, narcolepsy, chronicfatigue syndrome, seasonal affective disorder, premenstrual syndrome,substance addiction or abuse, and nicotine addiction.

[0029] As used herein, the term “substance addiction” includes, but isnot limited to, addiction to cocaine, heroin, nicotine, alcohol,opioids, anxiolytic and hypnotic drugs, cannabis (marijuana),amphetamines, hallucinogens, phencyclidine, volatile solvents, andvolatile nitrites. Nicotine addiction includes nicotine addiction of allknown forms, such as smoking cigarettes, cigars and/or pipes, andaddiction to chewing tobacco.

[0030] As used herein, the terms “attention deficit disorder” (ADD),“attention deficit disorder with hyperactivity” (ADDH), and “attentiondeficit/hyperactivity disorder” (AD/HD), are used in accordance withtheir accepted meanings in the art. See, e.g., Diagnostic andStatistical Manual of Mental Disorders, Fourth Ed., American PsychiatricAssociation, 1997 (DSM-IV™) and Diagnostic and Statistical Manual ofMental Disorders, 3^(rd) Ed., American Psychiatric Association (1981)(DSM-III™).

[0031] As used herein, the term “depression” includes a disease orcondition characterized by changes in mood, feelings of intense sadness,despair, mental slowing, loss of concentration, pessimistic worry,agitation, and self-deprecation. Physical symptoms of depression thatmay be reduced or alleviated by the methods of the invention includeinsomnia, anorexia, weight loss, decreased energy and libido, andabnormal hormonal circadian rhythms.

[0032] As used herein, the term “cerebral function disorder” includes,but is not limited to, cerebral function disorders involvingintellectual deficits such as senile dementia, Alzheimer's typedementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbancesof consciousness, coma, lowering of attention, speech disorders,Parkinson's disease, Lennox syndrome, autism, hyperkinetic syndrome andschizophrenia. Also within the meaning of the term are disorders causedby cerebrovascular diseases including, but not limited to, cerebralinfarction, cerebral bleeding, cerebral arteriosclerosis, cerebralvenous thrombosis, head injuries, and the like where symptoms includedisturbance of consciousness, senile dementia, coma, lowering ofattention, and speech disorders.

[0033] As used herein, the term “method of treating Parkinson's disease”means relief from the symptoms of Parkinson's disease which include, butare not limited to, slowly increasing disability in purposeful movement,tremors, bradykinesia, rigidity, and a disturbance of posture.

[0034] As used herein, the term “a method fortreating obesity or weightgain” means reduction of weight, relief from being overweight, relieffrom gaining weight, or relief from obesity, all of which are usuallydue to extensive consumption of food.

[0035] As used herein, the term “a method of treating or preventingincontinence” means prevention of or relief from the symptoms ofincontinence including involuntary voiding of feces or urine, anddribbling or leakage or feces or urine which may be due to one or morecauses including, but not limited to, pathology altering sphinctercontrol, loss of cognitive function, overdistention of the bladder,hyper-reflexia and/or involuntary urethral relaxation, weakness of themuscles associated with the bladder, or neurologic abnormalities. Asused herein, the term “urinary incontinence” encompasses stress urinaryincontinence and urge urinary incontinence.

DETAILED DESCRIPTION OF THE INVENTION

[0036] This invention relates to methods and compositions that inhibitthe reuptake of neuronal monoamines (e.g., norepinephrine). Theinvention thereby provides methods, pharmaceutical compositions, anddosage forms for the treatment or prevention of disorders that areameliorated by the inhibition of neuronal monoamine reuptake including,but are not limited to, erectile dysfunction, affective disorders,cerebral function disorders, tobacco smoking, and incontinence.

[0037] The methods, pharmaceutical compositions, and dosage forms of theinvention comprise a bupropion metabolite or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof. Preferably the bupropionmetabolite is optically pure. More preferably, the bupropion metaboliteis optically pure (S,S)-hydroxybupropion (i.e.,(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol).

[0038] The bupropion metabolite (S,S)-hydroxybupropion is anunexpectedly selective norepinephrine reuptake inhibitor that does notsignificantly inhibit dopamine reuptake. It can thus be used to treat orprevent disorders related to norepinephrine reuptake without incurringadverse side effects associated with the inhibition of dopaminereuptake. It can also be used to treat or prevent disorders related tonorepinephrine reuptake while reducing or avoiding adverse effectsassociated with racemic bupropion.

[0039] A first embodiment of the invention is a method of treating orpreventing a disorder that is ameliorated by the inhibition of neuronalmonoamine reuptake which comprises administering to a patient in need ofsuch treatment or prevention a therapeutically or prophylacticallyeffective amount of a bupropion metabolite, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof. Preferably, thebupropion metabolite is optically pure. More preferably, the bupropionmetabolite is optically pure (S,S)-hydroxybupropion. In a preferredmethod encompassed by this embodiment, adverse effects associated withthe inhibition of dopamine reuptake are reduced or avoided.

[0040] In another preferred method encompassed by this embodiment, thebupropion metabolite or pharmaceutically acceptable salt, solvate, orclathrate thereof is adjunctively administered with an additionalpharmacologically active compound, i.e., the bupropion metabolite and anadditional pharmacologically active compound are administered as acombination, concurrently but separately, or sequentially by anysuitable route (e.g. orally, transdermally, or mucosally).

[0041] Additional pharmacologically active compounds include, but arenot limited to, SSRIs, 5-HT₃ inhibitors, and nicotine. Selectiveserotonin reuptake inhibitors are compounds that inhibit the centralnervous system uptake of serotonin while having reduced or limitedaffinity for other neurologically active receptors. Examples of SSRIsinclude, but are not limited to, citalopram (CELEXA®); fluoxetine(PROZAC®) fluvoxamine (LUVOX®); paroxetine (PAXIL®); sertraline(ZOLOFT®); venlafaxine (EFFEXOR®); and optically pure stereoisomers,active metabolites, and pharmaceutically acceptable salts, solvates, andclathrates thereof.

[0042] Preferred 5-HT₃ antagonists are antiemetic agents. Examples ofsuitable 5-HT₃ antagonists include, but are not limited to, granisetron(KYTRIL®), metoclopramide (REGLAN®), ondansetron (ZOFRAN®), renzapride,zacopride, tropisetron, and optically pure stereoisomers, activemetabolites, and pharmaceutically acceptable salts, solvates, andclathrates thereof.

[0043] A second embodiment of the invention encompasses a method oftreating or preventing erectile dysfunction which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a bupropionmetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof. Preferably, the bupropion metabolite is optically pure. Morepreferably, the bupropion metabolite is optically pure(S,S)-hydroxybupropion.

[0044] In a preferred method encompassed by this embodiment, thebupropion metabolite or pharmaceutically acceptable salt, solvate, orclathrate thereof is administered transdermally or mucosally (e.g.,nasally, sublingually, or buccally).

[0045] In another preferred method encompassed by this embodiment, thebupropion metabolite or pharmaceutically acceptable salt, solvate, orclathrate thereof is adjunctively administered with a 5-HT₃ antagonist.

[0046] A third embodiment of the invention encompasses a method oftreating or preventing an affective disorder which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a bupropionmetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof. Preferably, the bupropion metabolite is optically pure. Morepreferably, the bupropion metabolite is optically pure(S,S)-hydroxybupropion.

[0047] A particular preferred method encompassed by this embodiment is amethod of treating or preventing depression. Another preferred methodencompassed by this embodiment is a method of treating or preventingnarcolepsy. Yet another preferred method encompassed by this embodimentis a method of treating or preventing nicotine addiction.

[0048] A fourth embodiment of the invention encompasses a method oftreating or preventing a cerebral function disorder which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a bupropionmetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof. Preferably, the bupropion metabolite is optically pure. Morepreferably, the bupropion metabolite is optically pure(S,S)-hydroxybupropion.

[0049] A particular preferred method encompassed by this embodiment is amethod of treating or preventing Parkinson's disease. Another preferredmethod encompassed by this embodiment is a method of treating orpreventing epilepsy.

[0050] A fifth embodiment of the invention encompasses a method ofeliciting smoking cessation which comprises administering to a patientwho smokes tobacco a therapeutically effective amount of a bupropionmetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof. Preferably, the bupropion metabolite is optically pure. Morepreferably, the bupropion metabolite is optically pure(S,S)-hydroxybupropion.

[0051] In preferred method encompassed by this embodiment, the bupropionmetabolite or pharmaceutically acceptable salt, solvate, or clathratethereof is administered orally, mucosally, or transdermally. In a morepreferred method, the bupropion metabolite or pharmaceuticallyacceptable salt, solvate, or clathrate thereof is administeredtransdermally.

[0052] In another preferred method encompassed by this embodiment, thebupropion metabolite or pharmaceutically acceptable salt, solvate, orclathrate thereof is adjunctively administered with a therapeuticallyeffective amount of nicotine. Preferably, the nicotine and/or bupropionmetabolite or pharmaceutically acceptable salt, solvate, or clathratethereof is administered orally, mucosally, or transdermally. Morepreferably, the nicotine and/or bupropion metabolite or pharmaceuticallyacceptable salt, solvate, or clathrate thereof is administeredtransdermally.

[0053] A sixth embodiment of the invention encompasses a method oftreating or preventing incontinence which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a bupropion metabolite or apharmaceutically acceptable salt, solvate, or clathrate thereof.Preferably, the bupropion metabolite is optically pure. More preferably,the bupropion metabolite is optically pure (S,S)-hydroxybupropion. Apreferred method encompassed by this embodiment is a method of treatingor preventing stress urinary incontinence. In another preferred methodencompassed by this embodiment, the patient is a human of an age greaterthan 50 years or less than 13 years.

[0054] A seventh embodiment of the invention encompasses pharmaceuticalcompositions and dosage forms which comprise a bupropion metabolite or apharmaceutically acceptable salt, solvate, or clathrate thereof.Preferably, the bupropion metabolite is optically pure. More preferably,the bupropion metabolite is optically pure (S,S)-hydroxybupropion.

[0055] Pharmaceutical compositions and dosage forms encompassed by thisembodiment can further comprise at least one additionalpharmacologically active compound. Additional pharmacologically activecompounds include, but are not limited to, SSRIs, 5-HT₃ inhibitors, andnicotine as described above.

[0056] An eighth embodiment of the invention encompasses a process forpreparing optically pure (S,S)-hydroxybupropion which comprises: theasymmetric dihydroxylation ofZ-1-(3-chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene to form anintermediate; the reaction of the intermediate with2-amino-2-methyl-1-propanol to form(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; and theisolation of the(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.Preferably, the intermediate formed by the asymmetric dihydroxylation isan α-hydroxy ketone activated by trifluoromethane sulfonic anhydride.

[0057] A ninth embodiment of the invention encompasses a process forpreparing optically pure (R,R)-hydroxybupropion which comprises: theasymmetric dihydroxylation ofZ-1-(3-chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene to form anintermediate; the reaction of the intermediate with2-amino-2-methyl-1-propanol to form(R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; and theisolation of the(R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.Preferably, the intermediate formed by the asymmetric dihydroxylation isan a-hydroxy ketone activated by trifluoromethane sulfonic anhydride.

Synthesis of Bupropion Metabolites

[0058] The metabolism of bupropion, which varies among species, iscomplex and poorly understood. Bupropion has been shown to induce itsown metabolism in mice, rats, and dogs, and may do so in human patientsto whom the drug has been administered over long periods of time. In theplasma of healthy humans to which the drug has been administered,however, at least three major metabolites are found. Physicians' DeskReference® 1252-1258 (53^(rd ed.) 1999). Each of these major metabolitesis chiral, meaning that a total of at least ten optically pure bupropionmetabolites exist in varying concentrations in the plasma of a patientfollowing administration of the drug.

[0059] It is possible to prepare a mixture of the stereoisomers of theamino alcohol metabolite of bupropion (i.e.,1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]1-propanol) usingtechniques known to those skilled in the art. See, e.g., Japanese PatentNo. 63091352. The optically pure forms of this metabolite can beisolated from the resulting mixture by any method known to those skilledin the art, including high performance liquid chromatography (HPLC) andthe formation and crystallization of chiral salts. See, e.g., Jacques,J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience,New York, 1981); Wilen, S. H., et al., Tetrahedron, 33:2725 (1977);Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N.Y.,1962); and Wilen, S. H., Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind., 1972).

[0060] It is also possible to prepare a mixture of the stereoisomers ofthe tert-butyl alcohol metabolite of bupropion (i.e.,1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone). From theresulting mixture of compounds, individual stereoisomers may be resolvedusing conventional means such as HPLC and the formation andcrystallization of chiral salts.

[0061] Alleged analogues of the hydroxybupropion metabolite (i.e.,2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol) havereportedly been prepared according to methods known to those skilled inthe art. See, e.g., Kelly, J. L., et al., J. Med. Chem., 39:347-349(1996). Not until now, however, has an effective and efficient syntheticprocess been discovered for the synthesis of optically purestereoisomers of the metabolite itself. This process utilizes aprotected alcohol derivative of 1-(3-chlorophenyl)-1-propene, which isdihydroxylated and then cyclized to form the morpholinol moiety. Aparticular embodiment of this process which can be used to formoptically pure (R,R)- and (S,S)-hydroxybupropion is shown in Scheme 3:

[0062] According to a preferred embodiment of this process, compound 5is prepared in step (a), wherein the ketone 4 is converted to itsenolate, preferably by use of a strong base such as, but not limited to,lithium hexamethyldisilazide (LHMDS) and lithium diisopropylamide (LDA).A preferred base is LDA. The enolate is then trapped using a protectingagent such as, but not limited to, tert-butyl-dimethylsilyl chloride(TBSC1). Compound 5 is preferably isolated prior to step (b).

[0063] According to step (b), the vinyl group of compound 5 isasymmetrically dihydroxylated to give the ketone. It has been found thatthe choice of reagent used to asymmetrically hydroxylate compound 5affects the stereochemistry of the resulting product, as well as itsoptical purity. Suitable asymmetric hydroxylation reagents include, forexample, oxides of transition metals such as manganese and osmium,although preferred reagents are AD-mix-α and AD-mix-β. These reagentshave been found to selectively dihydroxylate the vinyl group of compound5 to reform the ketone. Use of AD-mix-α yields(R)-3-chloro-2-hydroxyl-propiophenone (i), while use of AD-mix-β yields(S)-3-chloro-2-hydroxyl-propiophenone. Although not necessary, it hasbeen found that care taken to ensure the optical purity of theintermediate (e.g., compound 6) formed in this step improves the opticalpurity of the final product (i.e., optically pure hydroxybupropion). Itis thus preferred that step (b) further include purification by, forexample, column chromatography.

[0064] Substantially optically pure (5,5)-hydroxybupropion 7 is formedin step (c) of Scheme 3, which comprises the stereospecific displacementof triflates of compound 6:

[0065] wherein R is triflate (i.e., —OSO₂CF₃). Other compoundspotentially useful in the synthesis of the compounds of the inventionare those wherein R is mesylate, tosylate, or nosylate. Substantiallyoptically pure (R,R)-hydroxybupropion is preferably formed from thetriflate of opposite stereochemistry.

[0066] Triflation is conducted with pyridine base. A preferred base islutidine when used in combination with trifluoromethanesulfonicanhydride. The cyclized product 7 is isolated by extraction, andpurified by chromatography. Substantially optically pure(R,R)-hydroxybupropion is formed in the same way if step (b) yields(S)-3-chloro-2-hydroxyl-propiophenone.

Biological Activities if Bupropion Metabolites

[0067] Bupropion metabolites can be screened for their ability toinhibit the reuptake of the neuronal monoamines norepinephrine (NE),dopamine (DA), and serotonin (5-HT). Norepinephrine reuptake inhibitioncan be determined using the general procedure described by Moisset, B.,et al., Brain Res., 92:157-164 (1975); dopamine reuptake inhibition canbe determined using the general procedures described by Janowsky, A., etal, J. Neurochem. 46:1272-1276 (1986); and serotonin reuptake inhibitioncan be determined using the general procedures described by Perovic, S.and Muller, W. E. G., Brain Res. 92:157-164 (1995).

Pharmaceutical Compositions and Method of use

[0068] The magnitude of a prophylactic or therapeutic dose of an activeingredient in the acute or chronic management of a disorder or conditionwill vary with the severity of the disorder or condition to be treatedand the route of administration. The dose, and perhaps the dosefrequency, will also vary according to age, body weight, response, andthe past medical history of the patient. Suitable dosing regimens can bereadily selected by those skilled in the art with due consideration ofsuch factors.

[0069] Suitable daily doses for the treatment or prevention of adisorder described herein can be readily determined by those skilled inthe art. A recommended dose of racemic or optically pure bupropionmetabolite is from about 1 mg to about 750 mg per day, given as a singleonce-a-day dose in the morning or as divided doses throughout the day.Preferably, a daily dose is from about 5 mg to about 700 mg per day,more preferably from about 10 mg to about 650 mg per day.

[0070] Suitable daily dosage ranges of second pharmacologically activecompounds that can be adjunctively administered with a racemic oroptically pure bupropion metabolite can be readily determined by thoseskilled in the art following dosages reported in the literature andrecommended in the Physician's Desk Reference® (53^(rd) ed., 1999).

[0071] For example, suitable daily dosage ranges of 5-HT₃ antagonistscan be readily determined by those skilled in the art and will varydepending on factors such as those described above and the particular5-IIT₃ antagonists used. In general, the total daily dose of a 5-HT₃antagonist for the treatment or prevention of a disorder describedherein is from about 0.5 mg to about 500 mg, preferably from about 1 mgto about 350 mg, and more preferably from about 2 mg to about 250 mg perday.

[0072] Suitable daily dosage ranges of nicotine can also be readilydetermined by those skilled in the art and will vary depending onfactors such as those described above. In general, the total daily doseof nicotine for the treatment or prevention of a disorder describedherein is from about 1 mg to about 60 mg, preferably from about 8 mg toabout 40 mg, and more preferably from about 10 mg to about 25 mg perday.

[0073] The therapeutic or prophylactic administration of an activeingredient of the invention is preferably initiated at a lower dose,e.g., from about 1 mg to about 75 mg of bupropion metabolite andoptionally from about 15 mg to about 60 mg of 5-HT₃ antagonist, andincreased, if necessary, up to the recommended daily dose as either asingle dose or as divided doses, depending on the global response of thepatient. It is further recommended that patients aged over 65 yearsshould receive doses of bupropion metabolite in the range of from about1 mg to about 375 mg per day depending on global response. It may benecessary to use dosages outside these ranges, which will be readilydeterminable by one of ordinary skill in the pharmaceutical art.

[0074] The dosage amounts and frequencies provided above are encompassedby the terms “therapeutically effective,” “prophylactically effective,”and “therapeutically or prophylactically effective” as used herein. Whenused in connection with an amount of a racemic or optically purebupropion metabolite, these terms further encompass an amount of racemicor optically pure bupropion metabolite that induces fewer or less severadverse effects than are associated with the administration of racemicbupropion.

[0075] Any suitable route of administration can be employed forproviding the patient with a therapeutically or prophylacticallyeffective dose of an active ingredient. For example, oral, mucosal(e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral (e.g.,intravenous, intramuscular), transdermal, and subcutaneous routes can beemployed. Preferred routes of administration include oral, transdermal,and mucosal. As mentioned above, administration of an active ingredientfor the treatment or prevention of erectile dysfunction is preferablymucosal or transdermal. Suitable dosage forms for such routes include,but are not limited to, transdermal patches, ophthalmic solutions,sprays, and aerosols. Transdermal compositions can also take the form ofcreams, lotions, and/or emulsions, which can be included in anappropriate adhesive for application to the skin or can be included in atransdermal patch of the matrix or reservoir type as are conventional inthe art for this purpose.

[0076] A preferred transdermal dosage form is a “reservoir type” or“matrix type” patch, which is applied to the skin and worn for aspecific period of time to permit the penetration of a desired amount ofactive ingredient. Examples of transdermal dosage forms and methods ofadministration that can be used to administer the active ingredient(s)of the invention include, but are not limited to, those disclosed inU.S. Pat. Nos.: 4,624,665; 4,655,767; 4,687,481; 4,797,284; 4,810,499;4,834,978; 4,877,618; 4,880,633; 4,917,895; 4,927,687; 4,956,171;5,035,894; 5,091,186; 5,163,899; 5,232,702; 5,234,690; 5,273,755;5,273,756; 5,308,625; 5,356,632; 5,358,715; 5,372,579; 5,421,816;5,466;465; 5,494,680; 5,505,958; 5,554,381; 5,560,922; 5,585,111;5,656,285; 5,667,798; 5,698,217; 5,741,511; 5,747,783; 5,770,219;5,814,599; 5,817,332; 5,833,647; 5,879,322; and 5,906,830, thedisclosures of which are incorporated herein by reference.

[0077] An example of a transdermal dosage form of the inventioncomprises a bupropion metabolite and/or a second pharmacologicallyactive compound in a patch form. The patch is worn for 24 hours andprovides a total daily dose of from about 1 mg to about 750 mg per day.Preferably, a daily dose is from about 5 mg to about 700 mg per day,more preferably, from about 10 mg to about 650 mg per day. The patch canbe replaced with a fresh patch when necessary to provide constantadministration of the active ingredient to the patient.

[0078] Other dosage forms of the invention include, but are not limitedto, tablets, coated tablets, caplets, troches, lozenges, dispersions,suspensions, suppositories, ointments, cataplasms (poultices), pastes,powders, dressings, creams, plasters, solutions, capsules, soft elasticgelatin capsules, sustained release formulations, and patches.

[0079] In one embodiment, pharmaceutical compositions and dosage formsof the invention comprise a racemic or optically pure bupropionmetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof, and optionally a second pharmacologically active compound, suchas a SSRI, a 5-HT₃ antagonist, or nictotine. Preferred racemic oroptically pure bupropion metabolites are(R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;(S,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;(R,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;(R,R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol;(S,R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol;(S,S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol;(R,S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol;(R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; and(S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone. Thepharmaceutical compositions and dosage forms can contain apharmaceutically acceptable carrier and optionally other therapeuticingredients known to those skilled in the art.

[0080] In practical use, an active ingredient can be combined in anintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier can takea wide variety of forms depending on the form of preparation desired foradministration. In preparing the compositions for an oral dosage form,any of the usual pharmaceutical media can be employed as carriers, suchas, for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, preferablywithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oral preparationsbeing preferred over the liquid preparations.

[0081] Because of their ease of administration, tablets and capsulesrepresent the most advantageous oral dosage unit forms, in which casesolid pharmaceutical carriers are employed. If desired, tablets can becoated by standard aqueous or nonaqueous techniques.

[0082] In addition to the common dosage forms set out above, an activeingredient can also be administered by controlled release means ordelivery devices that are well known to those of ordinary skill in theart, such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, thedisclosures of which are incorporated herein by reference. These dosageforms can be used to provide slow or controlled-release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, or microspheres or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled-release formulations known to those ofordinary skill in the art, including those described herein, can bereadily selected for use with the pharmaceutical compositions of theinvention. The invention thus encompasses single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled-release.

[0083] All controlled-release pharmaceutical products have a common goalof improving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include: 1) extended activity of the drug; 2) reduceddosage frequency; and 3) increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and thus can affect the occurrence of side effects.

[0084] Most controlled-release formulations are designed to initiallyrelease an amount of drug that promptly produces the desired therapeuticeffect, and gradually and continually release of other amounts of drugto maintain this level of therapeutic effect over an extended period oftime. In order to maintain this constant level of drug in the body, thedrug must be released from the dosage form at a rate that will replacethe amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousinducers, including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

[0085] Pharmaceutical compositions of the invention suitable for oraladministration can be presented as discrete dosage forms, such ascapsules, cachets, or tablets, or aerosol sprays each containing apredetermined amount of an active ingredient as a powder or in granules,a solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosageforms can be prepared by any of the methods of pharmacy, but all methodsinclude the step of bringing the active ingredient into association withthe carrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation.

[0086] For example, a tablet can be prepared by compression or molding,optionally with one or more accessory ingredients. Compressed tabletscan be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

[0087] This invention further encompasses lactose-free pharmaceuticalcompositions and dosage forms. Because the major human metabolites ofbupropion are secondary amines, they can potentially decompose over timewhen exposed to lactose. Compositions of the invention that comprisebupropion metabolites preferably contain little, if any, lactose othermono- or di-saccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.

[0088] Lactose-free compositions of the invention can compriseexcipients which are well known in the art and are listed in the USP(XXI)/NF (XVI), which is incorporated herein by reference. In general,lactose-free compositions comprise an active ingredient, abinder/filler, and a lubricant in pharmaceutically compatible andpharmaceutically acceptable amounts. Preferred lactose-free dosage formscomprise an active ingredient, microcrystalline cellulose,pre-gelatinized starch, and magnesium stearate.

[0089] This invention further encompasses anhydrous pharmaceuticalcompositions and dosage forms which comprises an active ingredient,since water can facilitate the degradation of some compounds. Forexample, the addition of water (e.g., 5%) is widely accepted in thepharmaceutical arts as a means of simulating long-term storage in orderto determine characteristics such as shelf-life or the stability offormulations over time. See, e.g., Jens T. Carstensen, Drug Stability:Principles & Practice, 2d. Ed., Marcel Dekker, New York, N.Y., 1995, pp.379-80. In effect, water and heat accelerate decomposition. Thus theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

[0090] Anhydrous pharmaceutical compositions and dosage forms of theinvention can be prepared using anhydrous or low moisture containingingredients and low moisture or low humidity conditions. Pharmaceuticalcompositions and dosage forms of racemic or optically pure bupropionmetabolite which contain lactose are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

[0091] An anhydrous pharmaceutical composition should be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions are preferably packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastic or the like, unit dosecontainers, blister packs, and strip packs.

[0092] In this regard, the invention encompasses a method of preparing asolid pharmaceutical formulation which comprises an active ingredientwhich method comprises admixing under anhydrous or low moisture/humidityconditions the active ingredient and an excipient (e.g., lactose),wherein the ingredients are substantially free of water. The method canfurther comprise packaging the anhydrous or non-hygroscopic solidformulation under low moisture conditions. By using such conditions, therisk of contact with water is reduced and the degradation of the activeingredient can be prevented or substantially reduced.

[0093] Binders suitable for use in pharmaceutical compositions anddosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0094] Suitable forms of microcrystalline cellulose include, forexample, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, and AVICEL-PH-105 (available from FMC Corporation, AmericanViscose Division, Avicel Sales, Marcus Hook, Pa., U.S.A.). An exemplarysuitable binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

[0095] Examples of suitable fillers for use in the pharmaceuticalcompositions and dosage forms disclosed herein include, but are notlimited to, talc, calcium carbonate (e.g., granules or powder),microcrystalline cellulose, powdered cellulose, dextrates, kaolin,mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, andmixtures thereof. The binder/filler in pharmaceutical compositions ofthe present invention is typically present in about 50 to about 99weight percent of the pharmaceutical composition.

[0096] Disintegrants are used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant will produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s)should be used to form the dosage forms of the compounds disclosedherein. The amount of disintegrant used varies based upon the type offormulation and mode of administration, and is readily discernible tothose of ordinary skill in the art. Typically, about 0.5 to about 15weight percent of disintegrant, preferably about 1 to about 5 weightpercent of disintegrant, can be used in the pharmaceutical composition.

[0097] Disintegrants that can be used to form pharmaceuticalcompositions and dosage forms of the invention include, but are notlimited to, agar-agar, alginic acid, calcium carbonate, microcrystallinecellulose, croscarmellose sodium, crospovidone, polacrilin potassium,sodium starch glycolate, potato or tapioca starch, other starches,pre-gelatinized starch, other starches, clays, other algins, othercelluloses, gums or mixtures thereof.

[0098] Lubricants which can be used to form pharmaceutical compositionsand dosage forms of the invention include, but are not limited to,calcium stearate, magnesium stearate, mineral oil, light mineral oil,glycerin, sorbitol, mannitol, polyethylene glycol, other glycols,stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil,corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate,agar, or mixtures thereof. Additional lubricants include, for example, asyloid silica gel (AEROSIL 200, manufactured by W. R. Grace Co. ofBaltimore, Md.), a coagulated aerosol of synthetic silica (marketed byDegussa Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxideproduct sold by Cabot Co. of Boston, Mass.), or mixtures thereof. Alubricant can optionally be added, typically in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

[0099] Dosage forms of the invention that comprise a bupropionmetabolite preferably contain from about 1 mg to about 750 mg of themetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof. For example, each tablet, cachet, or capsule contains fromabout 1 mg to about 750 mg of the active ingredient. Most preferably,the tablet, cachet, or capsule contains either one of three dosages,e.g., about 25 mg, about 50 mg, or about 75 mg of a racemic or opticallypure bupropion metabolite (as scored lactose-free tablets, thepreferable dose form).

[0100] The invention is further defined by reference to the followingexamples. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, can be practiced withoutdeparting from the scope of this invention.

EXAMPLES Example 1

[0101] Synthesis of (5,5)-Hydroxybupropion

[0102] This synthesis, which follows that depicted in Scheme 3 of theDetailed Description, comprises the formation of three intermediates.

[0103] Z-1-(3-Chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene. Asolution of LDA (33.0 mmol) in THF (100 mL) was cooled to −78° C. andHMPA (5 mL) was added. The ketone [1-(3-chlorophenyl)-propanone] (8.6 g)in THF (20 mL) was slowly added over 45 minutes to this rapidly stirringmixture. After an additional 3 minutes at −78° C., TBSCI (33.0 mL, 1.0 Min hexane) was added. This mixture was stirred at −78° C. for 5 minutesand allowed to warm to room temperature over 40 minutes. NaHCO₃ (60 mL,saturated aqueous solution) was added and the mixture was extracted withCH₂Cl₂ (2×80 mL). The organic extracts were combined, washed with brine,dried over Mg₂SO₄ and concentrated to give a crude mixture. The productwas purified by flash chromatography eluted with hexane/TEA (99.5/0.5),yielding 13.4 g product (ZIE ratio>99). ¹H NMR(CDCl₃): δ0.12 (s, 6H),0.95 (s, 9H), 2.75 (d, 3H), 5.25 (q, 1H), 7.2-7.42 (m, 4H).

[0104] (R)-3′-Chloro-2-hydroxyl-propiophenone.Z-1-(3-Chlorophenyl-tert-butyldimethylsilyloxy-1-propene (12.0 g, 44mmol) was added to a well-stirred mixture of AD-mix-P (80 g) andCH₃SO₂NH₂ (4.2 g, 44 mmol) in tert-butyl alcohol/water mixture (220mL/220 mL) maintained at 0° C. The reaction mixture was stirred at 0° C.for 28 hours. Solid sodium sulfite (40 g) was added. The mixture wasstirred for an additional 45 minutes and extracted with CH₂Cl₂ (2×100mL). The combined organic extracts were washed with NaHCO₃ and brine,and evaporated. The residue was passed through a silica gel column togive the desired product (7.0 g). ¹H NMR (CDCl₃): δ1.45 (d, 3H), 5.15(q, 1H), 7.2-7.9 (m, 4H).

[0105] (S,S)-Hydroxybupropion. To a solution of(R)-3′-chloro-2-hydroxyl-propiophenone (300 mg) in CH₂Cl₂ (6 mL) at −78°C. was added trifluoromethanesulfonic anhydride (0.5 g), followed byaddition of 2,6-lutidine (0.26 g). The reaction mixture was allowed towarm to −40° C. and stirred at this temperature for 40 minutes.2-Amine-2-methyl-1-propanol (0.4 g, 2.5 eq) was added, and stirred for 2hours at −40° C. The reaction mixture was warmed to room temperature andstirred overnight. It was extracted with CH₂Cl₂ (10 mL). The extract waswashed with NaHCO₃, water, and brine, concentrated to give a residue.The final product was purified by chromatography eluted with CH₃CN (180mg, e.e. >99%). ¹H NMR (CDCl₃) δ0.78 (d, 3H), 1.1 (s, 3H), 1.4 (s, 3H),3.2 (q, 1H), 3.4 (d, 1H), 3.8 (d, 2H), 7.2-7.65 (m, 4H). [a]=+66°(c=1,EtOH). (5,5)-hydroxybupropion free base was treated with HCl in diethylether to give its HCl salt. [a]=±30.6°(c=1, EtOH). ¹H NMR (DMSO-_(d6))δ1.0 (d, 3H), 1.32 (s, 3H), 1.56 (s, 3H), 3.4 (s, 1H), 3.4 (d, 1H), 4.0(d, 1H), 7.5 (m, 5H), 8.8 (s, 1H), 10.1 (s, 1H). e.e. 99.4% asdetermined by HPLC with chiral column, ChiralCEl GD. 4.6×250 mm, 10 nm,hexane/ethanol/diethylamine (98:2:0.1). (R,R)-hydroxybupropion wasprepared from (S)-3′-chloro-2-hydroxyl-propiophenone with 97% e.e. asdetermined by HPLC with chiral column, ChiralCEl GD. 4.6×250 mm, 10 nm,hexane/ethanol/diethylamine (98:2:0.1).

Example 2

[0106] Neuronal Monoamine Reuptake Inhibition

[0107] The abilities of racemic bupropion [BP(±)], and the bupropionmetabolites (S,S)-hydroxybupropion [HBP(S,S)], (R,S)-hydroxybupropion[HBP(R,S)], and (RS,RS)-hydroxybupropion [HBP(RS,RS)] to inhibit thereuptake of neuronal monoamines was determined using the general methodsof Moisset, B., et al., Brain Res. 92:157-164 (1975), Janowsky, A., etal., J. Neurochem. 46:1272-1276 (1986), and Perovic, S. and Muller, W.E. G., Brain Res. 92:157-164 (1995).

[0108] Inhibition of norepinephrine (NE) reuptake was determined usingrat hypothalamus as a tissue source and protryptiline as a referencecompound. Inhibition of dopamine (DA) reuptake was determined using ratcorpora striata as a tissue source and GBR 12909 as a referencecompound. Inhibition of serotonin (5-HT) reuptake was determined usingrat brain as a tissue source and imipramine as a reference compound. Thespecific conditions for each assay are shown in Table 1: TABLE 1 AssaySubstrate Incubation Detection Method NE [³H]NE (0.2 μCi/mL) 20 min. /37° C. liquid scintillation DA [³H]DA (0.2 μCi/mL) 15 min. / 37° C.liquid scintillation 5-HT [³H]5-HT (0.2 μCi/mL) 15 min. / 37° C. liquidscintillation

[0109] wherein the end products observed were formed by theincorporation of [³H]NE, [³H]DA, and [³H]5-HT into synaptosomes.Radioactivity was determined with a scintillation counter (Topcount,Packard) using a liquid scintillation cocktail (Microscint 0, Packard).

[0110] Racemic bupropion and the bupropion metabolites were first testedin each assay at 10 μM in duplicate or triplicate. For assays whereinthey inhibited the reuptake by more than 50% at this concentration, theywere further tested at eight concentrations in duplicate to obtain fullinhibition curves. In each experiment, the respective reference compoundwas tested at eight concentrations in duplicate to obtain an inhibitioncurve in order to validate this experiment.

[0111] IC₅₀ values and Hill coefficients (nH) were determined for thereference compounds and the test compounds (i.e., bupropion andmetabolites of bupropion) by non-linear regression analysis of theirinhibition curves. These parameters were obtained by Hill equation curvefitting.

[0112] None of the compound tested significantly inhibited 5-HTreuptake. The IC₅₀ values determined for these compounds with regard tonorepinephrine and dopamine reuptake are presented in Table 2: TABLE 2NE reuptake DA reuptake Compounds IC₅₀ (nM) (nH) IC₅₀ (nM) (nH) HBP(S,S)229 (0.8) 1,400 (1.0) BP(±) 756 (1.1) HBP(R,S) 746 (>3) 294 (0.9)HBP(R,R) — — protriptyline 3.6/3.8 (2.6)/(1.4) GBR 12909 5.6 (1.7)

[0113] The measured biological activity of the bupropion metabolites areunexpectedly different than the activity of bupropion itself. Forexample, racemic bupropion (i.e.,(±)1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone) inhibitsnorepinephrine reuptake with an IC₅₀ of approximately 746 nM, while theoptically pure metabolite (S,S)-hydroxybupropion (i.e.,(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol) inhibitsnorepinephrine with a dramatically lower IC₅₀ of 229 nM. And whileracemic bupropion inhibits dopamine reuptake with an IC₅₀ ofapproximately 294 nM, the optically pure metabolite(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol does notsignificantly inhibit dopamine reuptake, having an IC₅₀ of approximately1400 nM. But like racemic bupropion, this optically pure metabolite doesnot measurably inhibit serotonin reuptake.

[0114] These results indicate that the biological activity of each ofthe bupropion metabolites of the invention is dramatically andunexpectedly different from that of bupropion. These results furtherindicate that bupropion metabolites are superior in their abilities totreat certain disorders. For example, optically pure(5,5)-hydroxybupropion is surprisingly selective with regard to itsinhibition of neuronal monoamine reuptake, and may thus be used toinhibit norepinephrine reuptake.

Example 3

[0115] In Vivi Activity: Seizure Model

[0116] The pharmacological effects of a bupropion metabolite can bedetermined in a number of ways. For example, its ability to inhibitartificially induced seizures in mice may be informative.

[0117] Using the methods of Green and Murray, J. Pharm. Pharmacol.41:879-880 (1989), a group of 4-6 rats are lightly restrained and a 10mg/mL solution of the convulsant drug pentetrazol is infused via a 25gauge needle inserted into a tail vein of each rat at a rate of 2.6mL/min. The time of infusion of the convulsant drug required to producethe first myoclonic twitch (which occurs with the first EEG abnormality)is recorded and doses required to produce the seizure calculated.Seizure threshold is expressed as mg/kg and can be calculated using theformula:

(I×C×T)/(60×W)

[0118] wherein I is the infusion rate measured in mL per minute; C isthe drug concentration in 10 mg/mL; T is the time to twitch in seconds;and W is the rate weight in kilograms.

[0119] Bupropion metabolites are administered by intraperitoneal orintravenous injection 15 minutes before the determination of seizurethreshold.

Example 4

[0120] In Vivo Activity: Phenylquinone Writhing Assay

[0121] The pharmacological effects of a bupropion metabolite can also bedetermined from the antiphenylquinone writhing test, which is a standardprocedure for detecting and comparing analgesic activity in laboratoryanimals. The advantage of this test is that it generally correlates wellwith human efficacy. In response to an injected, locally irritatingsolution, the animals have writhings that are inhibited by analgesicagents.

[0122] Mice dosed with at least two dose levels of a bupropionmetabolite are challenged with phenyl-p-benzoquinone (PPQ) givenintraperitoneally and then observed for the characteristicstretch-writhing syndrome. Lack of writhing constitutes a positiveresponse. The degree of analgesic protection can be calculated on thebasis of suppression of writhing relative to control animals run on thesame day. Time response data are also obtained. Observations are madeearly enough after dosing to detect differences in onset.

[0123] For example, the following protocols may be used, wherein tenmice are used per dose group:

[0124] Preparation of Phenylquinone: PPQ is made-up as a 0.02% aqueoussolution in ethyl alcohol. PPQ (20 mg) is ground and dissolved in atissue homogenizer in 5 mL ethyl alcohol, and the volume brought to 100mL with distilled water, preheated to 45° C. The resulting solutionshould be a clear amber color. PPQ solutions are made fresh twice dailyand, if necessary, about every four hours because of the tendency of PPQto precipitate out of solution.

[0125] Dose amounts: 0.1, 0.3, 1.0, 3.0, 10.0, 30.0, and 100.0 mg/kg.

[0126] Positive Control: Aspirin-200 mg/kg.

[0127] Writhing: PPQ solution is administered intraperitoneally using a25 gauge, ⅝″ long needle on a 1 mL syringe. Each animal in the groupreceives 0.25 mL. The group often mice per dose level is observedclosely for ten minutes for exhibition of writhing. The stability of thePPQ solution(s) to produce the writhing response is verified for eachpreparation in ten mice to which the vehicle was administered prior toPPQ administration.

[0128] Characteristic patterns of writhing consist of torsion of theabdomen and thorax, drawing the hind legs close to the body and raisingthe heels of the hind feet off of the floor.

[0129] Observation Times: Reference and positive control articleactivity is studied at 60 minutes after administration. After thedesignated absorption time interval of a group has elapsed, the mice arechallenged with PPQ. Each mouse receives one dose of 0.25 mL of PPQ.After PPQ administration, the mouse is placed in individual Plexiglas®squares 4″×4″×5″ deep and observed closely for a ten minute period forexhibition of the writhing syndrome.

[0130] Scoring Determinations: The total number of writhes for eachmouse is recorded. The mean number of writhes for the control and eachpositive control and reference group is compared and percent inhibitioncalculated.

Example 5

[0131] In Vivo Activity: Formalin Test

[0132] The pharmacological effects of a bupropion metabolite may also bedetermined from other models, some of which are discussed by Bannon, A.W., et al., Science 279:77-81 (1998). One of these models is theformalin test.

[0133] The formalin test is an animal model for persistent inflammatorypain. In the formalin test, the second phase of the biphasic nociceptiveresponse is thought to be mediated in part by a sensitization ofneuronal function at the level of the spinal cord, and reflect theclinical observation of hyperalgesia associated with tissue injury.

[0134] Using the method of Dubusson, D., and Dennis, S. G., Science4:161 (1977), rats are allowed to acclimate to their individual cagesfor 20 minutes, after which time 50 mL of a 5% formalin solution isinjected into the dorsal aspect of one of the rear paws. The rats arethen returned to the clear observation cages, which are suspended abovemirror panels. Only phase 2 of the formalin test may be scored, andphase 2 may be defined as the 20-minute period of time from 30 to 50minutes after formalin injection. The investigator records nocifensivebehaviors in the injected paw of four animals during the session byobserving each animal for one 15-second observation period during each1-minute interval. Nocifensive behaviors include flinching, licking, orbiting the injected paw. In dose-response studies, the test compound (orsaline) is administered 5 minutes before the injection of formalin. Inantagonist studies, the antagonists or saline are administered 10minutes before treatment.

Example 6

[0135] In Vivo Activity: Neuropathic Pain Model

[0136] Another pharmacological model discussed by Bannon, A. W., et al.,Science 279:77-81(1998) is the neuropathic pain test. In the neuropathicpain model, nerve injury results in neuroplastic changes that lead toallodynia, a condition characterized by nocifensive behavioral responsesto what are normally non-noxious stimuli conducted by Aβ fibers. In theChung model of neuropathic pain, allodynia is produced in the hind limbipsilateral by ligation of the LS and L6 spinal nerves. S. H. Kim and J.M. Chung, Science 50, 355 (1992). According to this model, awithin-subjects design in which all animals receive all treatments isused for dose-response studies.

[0137] Using the Chung model, baseline allodynia scores are determinedfor all animals before the start of the drug studies. Only rats withthreshold scores are considered allodynic and used in further testing.Drug studies (separate studies for each compound) begin approximately 2weeks after nerve ligation surgery. For dose-response experiments,animals are tested over a 2-week period. Test days are separated by 2 to3 day intervals during which no testing is conducted and no treatment isgiven. On test days, animals are placed in individual chambers andallowed to acclimate for 15 to 20 minutes. After acclimation, baselinescores are determined. Next, animals are treated and scores aredetermined 15, 30, 50, and 120 minutes after treatment. This procedureis repeated on test days until each animal has received all treatmentsfor any given drug. The treatment order is counterbalanced acrossanimals. For statistical analysis, the time point of peak effect iscompared.

Example 7

[0138] Oral Formulation

[0139] Table 3 provides the ingredients for a lactose-free tablet dosageform of a bupropion metabolite: TABLE 3 Component Quantity per Tablet(mg) Bupropion metabolite  75 (e.g., (S,S)-hydroxybupropion)Microcrystalline cellulose 125 Talc  5.0 Water (per thousand tablets) 30.0 mL * Magnesium Stearate  0.5

[0140] The active ingredient (bupropion metabolite) is blended with thecellulose until a uniform blend is formed. The smaller quantity of cornstarch is blended with a suitable quantity of water to form a cornstarch paste. This is then mixed with the uniform blend until a uniformwet mass is formed. The remaining corn starch is added to the resultingwet mass and mixed until uniform granules are obtained. The granules arethen screened through a suitable milling machine, using a ¼ inchstainless steel screen. The milled granules are then dried in a suitabledrying oven until the desired moisture content is obtained. The driedgranules are then milled through a suitable milling machine using ¼ meshstainless steel screen. The magnesium stearate is then blended and theresulting mixture is compressed into tablets of desired shape,thickness, hardness and disintegration Tablets are coated by standardaqueous or nonaqueous techniques.

[0141] Another tablet dosage formulation suitable for use with theactive ingredients of the invention is provided by Table 4: TABLE 4Quantity per Tablet (mg) Component Formula A Formula B Formula CBupropion metabolite 20 40 100 (e.g., (S,S)-hydroxybupropion)Microcrystalline cellulose 134.5 114.5 309.0 Starch BP 30 30 60Pregelatinized Maize Starch BP 15 15 30 Magnesium Stearate 0.5 0.5 1.0Compression Weight 200 200 500

[0142] The active ingredient is sieved and blended with cellulose,starch, and pregelatinized maize starch. Suitable volumes of purifiedwater are added and the powders are granulated. After drying, thegranules are screened and blended with the magnesium stearate. Thegranules are then compressed into tablets using punches.

[0143] Tablets of other strengths may be prepared by altering the ratioof active ingredient to pharmaceutically acceptable carrier, thecompression weight, or by using different punches.

Example 8

[0144] Oral Formulation

[0145] Table 5 provides the ingredients for a capsule dosage form of abupropion metabolite: TABLE 5 Quantity per Tablet (mg) Component FormulaA Formula B Formula C Bupropion metabolite 25 50 75 (e.g.,(S,S)-hydroxybupropion) Microcrystalline cellulose 149.5 124.5 374 CornStarch 25 25 50 Water (per thousand tablets) 0.5 0.5 1.0 MagnesiumStearate 200 200 200

[0146] The active ingredient, cellulose, and corn starch are blendeduntil uniform; then the magnesium stearate is blended into the resultingpowder. The resulting mixture is encapsulated into suitably sizedtwo-piece hard gelatin capsules using suitable machinery. Other dosescan be prepared by altering the ratio of active ingredient topharmaceutically acceptable carrier, the fill weight, and, if necessary,by changing the capsule size to suit.

[0147] The active ingredient, cellulose, and corn starch are blendeduntil uniform; then the magnesium stearate is blended into the resultingpowder. The resulting mixture is encapsulated into suitably sizedtwo-piece hard gelatin capsules using suitable machinery. Other dosescan be prepared by altering the ratio of active ingredient topharmaceutically acceptable carrier, the fill weight, and, if necessary,by changing the capsule size to suit.

[0148] The embodiments of the invention described above are intended tobe merely exemplary and those skilled in the art will recognize, or beable to ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the invention andare encompassed by the following claims.

What is claimed is:
 1. A method of treating or preventing a disorderthat is ameliorated by the inhibition of neuronal monoamine reuptakewhich comprises administering to a patient in need of such treatment orprevention a therapeutically or prophylactically effective amount of abupropion metabolite, or a pharmaceutically acceptable salt, solvate, orclathrate thereof.
 2. The method of claim 1 wherein the bupropionmetabolite is optically pure.
 3. The method of claim 2 wherein theoptically pure bupropion metabolite is optically pure(S,S)-hydroxybupropion.
 4. The method of claim 1 wherein the adverseeffects associated with the inhibition of dopamine reuptake are reducedor avoided.
 5. The method of claim 1 wherein the bupropion metabolite orpharmaceutically acceptable salt, solvate, or clathrate thereof isadjunctively administered with a second pharmacologically activecompound.
 6. A method of treating or preventing erectile dysfunctionwhich comprises administering to a patient in need of such treatment orprevention a therapeutically or prophylactically effective amount of abupropion metabolite or a pharmaceutically acceptable salt, solvate, orclathrate thereof.
 7. The method of claim 6 wherein the bupropionmetabolite is optically pure.
 8. The method of claim 7 wherein theoptically pure bupropion metabolite is optically pure(S,S)-hydroxybupropion.
 9. The method of claim 6 wherein the bupropionmetabolite or pharmaceutically acceptable salt, solvate, or clathratethereof is administered transdermally or mucosally.
 10. The method ofclaim 6 wherein the bupropion metabolite or pharmaceutically acceptablesalt, solvate, or clathrate thereof is adjunctively administered with a5-HT₃ antagonist.
 11. The method of claim 10 wherein the 5-HT₃antagonist is an antiemetic agent.
 12. The method of claim 10 whereinthe 5-HT₃ antagonist is selected from the group consisting ofgranisetron, metoclopramide, ondansetron, renzapride, zacopride,tropisetron, and optically pure stereoisomers, active metabolites, andpharmaceutically acceptable salts, solvates, and clathrates thereof. 13.A method of treating or preventing an affective disorder which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a bupropionmetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof.
 14. The method of claim 13 wherein the bupropion metabolite isoptically pure.
 15. The method of claim 14 wherein the optically purebupropion metabolite is optically pure (S,S)-hydroxybupropion.
 16. Themethod of claim 13 wherein the bupropion metabolite or pharmaceuticallyacceptable salt, solvate, or clathrate thereof is adjunctivelyadministered with a therapeutically or prophylactically effective amountof a second pharmacologically active compound.
 17. The method of claim13 wherein the affective disorder is depression.
 18. The method of claim13 wherein the affective disorder is narcolepsy.
 19. The method of claim13 wherein the affective disorder is nicotine addiction.
 20. A method oftreating or preventing a cerebral function disorder which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a bupropionmetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof.
 21. The method of claim 20 wherein the bupropion metabolite isoptically pure.
 22. The method of claim 21 wherein the optically purebupropion metabolite is optically pure (S,S)-hydroxybupropion.
 23. Themethod of claim 20 wherein the the bupropion metabolite orpharmaceutically acceptable salt, solvate, or clathrate thereof isadjunctively administered with a therapeutically or prophylacticallyeffective amount of a second pharmacologically active compound.
 24. Themethod of claim 20 wherein the cerebral function disorder is Parkinson'sdisease.
 25. The method of claim 20 wherein the cerebral functiondisorder is epilepsy.
 26. A method of eliciting smoking cessation whichcomprises administering to a patient who smokes tobacco atherapeutically effective amount of a bupropion metabolite or apharmaceutically acceptable salt, solvate, or clathrate thereof.
 27. Themethod of claim 26 wherein the bupropion metabolite is optically pure.28. The method of claim 27 wherein the optically pure bupropionmetabolite is optically pure (S,S)-hydroxybupropion.
 29. The method ofclaim 26 wherein the bupropion metabolite or pharmaceutically acceptablesalt, solvate, or clathrate thereof is administered orally, mucosally,or transdermally.
 30. The method of claim 29 wherein the bupropionmetabolite or pharmaceutically acceptable salt, solvate, or clathratethereof is administered transdermally.
 31. The method of claim 26wherein the bupropion metabolite or pharmaceutically acceptable salt,solvate, or clathrate thereof is adjunctively administered with atherapeutically effective amount of nicotine.
 32. The method of claim 31wherein the nicotine and/or bupropion metabolite or pharmaceuticallyacceptable salt, solvate, or clathrate thereof is administered orally,mucosally, or transdermally.
 33. The method of claim 32 wherein thenicotine and/or bupropion metabolite or pharmaceutically acceptablesalt, solvate, or clathrate thereof is administered transdermally.
 34. Amethod of treating or preventing incontinence which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a bupropionmetabolite or a pharmaceutically acceptable salt, solvate, or clathratethereof.
 35. The method of claim 34 wherein the bupropion metabolite isoptically pure.
 36. The method of claim 35 wherein the optically purebupropion metabolite is optically pure (S,S)-hydroxybupropion.
 37. Themethod of claim 34 wherein incontinence is stress urinary incontinence.38. The method of claim 34 wherein the patient is a human of an agegreater than 50 years or less than 13 years.
 39. A pharmaceuticalcomposition which comprises a bupropion metabolite or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof.
 40. The pharmaceuticalcomposition of claim 39 wherein the bupropion metabolite is opticallypure.
 41. The pharmaceutical composition of claim 40 wherein theoptically pure bupropion metabolite is optically pure(S,S)-hydroxybupropion.
 42. The pharmaceutical composition of claim 40wherein said pharmaceutical composition further comprises a secondpharmacologically active compound selected from the group consisting ofselective serotonin reuptake inhibitors, 5-IIT₃ inhibitors, andnicotine.
 43. A dosage form comprising a bupropion metabolite or apharmaceutically acceptable salt, solvate, or clathrate thereof.
 44. Thedosage form of claim 43 wherein said dosage form is solid.
 45. Thedosage form of claim 43 wherein said dosage form is a sterile solution.46. The dosage form of claim 43 wherein said dosage form is atransdermal patch.
 47. The dosage form of claim 43 wherein the bupropionmetabolite is optically pure.
 48. The dosage form of claim 47 whereinthe optically pure bupropion metabolite is optically pure(S,S)-hydroxybupropion.
 49. The dosage form of claim 43 wherein saiddosage form further comprises a second pharmacologically active compoundselected from the group consisting of selective serotonin reuptakeinhibitors, 5-HT₃ inhibitors, and nicotine.
 50. The dosage form of claim43 wherein said dosage form is suitable for oral, mucosal, ortransdermal administration to a patient.
 51. A dosage form suitable fortransdermal administration to a patient which comprises nicotine and abupropion metabolite or pharmaceutically acceptable salt, solvate, orclathrate thereof.
 52. A lactose-free solid dosage form comprising anoptically pure bupropion metabolite or a pharmaceutically acceptablesalt, solvate, or clathrate thereof.
 53. The dosage form of claim 52wherein said dosage form is an oral dosage form.
 54. A process forpreparing optically pure(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol or apharmaceutically acceptable salt, solvate or clathrate thereof whichcomprises: asymmetrically hydroxylatingZ-1-(3-chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene to form anintermediate; reacting the intermediate with 2-amino-2-methyl-1-propanolto form (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;and isolating the(S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.
 55. Aprocess for preparing optically pure(R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol or apharmaceutically acceptable salt, solvate or clathrate thereof whichcomprises: asymmetrically hydroxylatingZ-1-(3-chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene to form anintermediate; reacting the intermediate with 2-amino-2-methyl-1-propanolto form (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;and isolating the(R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.
 56. Theprocess of claim 54 or 55 wherein the intermediate formed by theasymmetric hydroxylation ofZ-1-(3-chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene is ana-hydroxy ketone activated by trifluoromethane sulfonic anhydride.
 57. Acompound of the formula:

wherein R is selected from the group consisting of hydrogen, triflate,tosylate, and nosylate; or a pharmaceutically acceptable salt, solvate,or clathrate thereof.